Alzheimer's Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the β-amyloid peptide (βAP) or sometimes Aβ, AβP or β/A4. β-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al. (Biochem. Biophys. Res. Commun., 120: 885-890) 1984)). β-amyloid peptide is a small fragment of a much larger precursor protein (APP), normally produced by cells in tissues of various animals.
Aβ is derived from cleavage of APP by protease systems, collectively termed secretases. APP is first cleaved by β secretase to yield a β stub, which is then cleaved by γ secretase to yield a β-amyloid fragment that is secreted. β secretase generates the N-terminus of Aβ. γ secretase generates C-terminal fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors that are subsequently truncated to the above polypeptides.
U.S. Pat. No. 6,153,652 discloses N-(aryl/heteroaryl/alkyacetyl)amino acid amides, which inhibit β amyloid peptide release and/or its synthesis, and methods for treating Alzheimer's disease with such compounds. U.S. Pat. Nos. 6,191,166 and 6,211,235 each discloses a class of compounds, which inhibit β amyloid peptide release and/or its synthesis, and methods for treating Alzheimer's disease with such compounds. WO 00/38618 discloses succinoylaminobenzodiazepines and related structures and methods for inhibiting γ-secretase activity. WO 00/77030 discloses statine-derived tetrapeptide inhibitors of beta-secretase. WO 99/66934 discloses certain cyclic amino acid compounds that inhibit β-amyloid peptide release and/or its synthesis and methods for treating Alzheimer's disease with such compounds.
Despite the progress which has been made in understanding the underlying mechanisms of AD and other β-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease. The treatment methods could be based on drugs that are capable of inhibiting β-amyloid peptide release and/or its synthesis in vivo. Methods of treatment could target the formation of Aβ through the enzymes involved in the proteolytic processing of β-amyloid precursor protein. Compounds that inhibit γ-secretase activity, either directly or indirectly, control the production of AP. Such inhibition of γ secretase could thereby reduce production of Aβ, which, thereby, reduces or prevents the neurological disorders associated with β-amyloid peptide.